Modified norcantharidins; synthesis, protein phosphatases 1 and 2A inhibition, and anticancer activity

Bioorg Med Chem Lett. 2004 Apr 19;14(8):1969-73. doi: 10.1016/j.bmcl.2004.01.093.


Fourteen modified norcantharidin analogues have been synthesised and screened for their ability to inhibit the serine/threonine protein phosphatases 1 and 2A. The most potent compounds found were 10 (PP1 IC(50)=13+/-5 microM; PP2A IC(50)=7+/-3 microM) and 16 (PP1 IC(50)=18+/-8 microM; PP2A IC(50)=3.2+/-0.4 microM). Overall, only analogues possessing at least one acidic residue at the former anhydride warhead displayed any PP1 or PP2A inhibitory action. The ability of these analogues to inhibit PP1 and PP2A correlates well with their observed anti-cancer activity against a panel of five cancer cell lines: A2780 (human ovarian carcinoma), G401 (human kidney carcinoma), HT29 (human colorectal carcinoma), H460 (human lung carcinoma) and L1210 (murine leukemia).

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / pharmacology*
  • Bridged Bicyclo Compounds, Heterocyclic / chemical synthesis*
  • Bridged Bicyclo Compounds, Heterocyclic / chemistry*
  • Bridged Bicyclo Compounds, Heterocyclic / pharmacology*
  • Cell Division / drug effects
  • Cell Line, Tumor
  • Drug Screening Assays, Antitumor
  • Humans
  • Molecular Structure
  • Phosphoprotein Phosphatases / antagonists & inhibitors*


  • Antineoplastic Agents
  • Bridged Bicyclo Compounds, Heterocyclic
  • norcantharidin
  • Phosphoprotein Phosphatases